Distinctive response of naïve lymphocytes from cord blood to primary activation via TCR

Abstract

Umbilical cord blood (UCB) is now being considered an alternative to bone marrow for restoring hematopoiesis after myeloablative therapy. The lower risk of acute and chronic graft-versus-host disease in patients who received UCB cells seems related to the nature of UCB-T cells. Phenotypically, UCB-CD3+ cells are mostly naive (CD45RA+) and represent a transitional population between thymocytes and adult T cells. We examined the immune reactivity of highly purified, negatively selected CD4+CD45RA+ cells by mimicking activation via T cell receptor (TCR). All experiments included the extensively characterized adult peripheral blood (APB) cells as reference. On the contrary to APB, naive UCB-CD4+ cells were able to proliferate with anti-CD3 stimulation alone. With addition of interleukin (IL)-2 or costimulatory signal, both populations reached similar proliferation. Forty-eight hours after anti-CD3 stimulation, CD4+CD45RA+ from UCB, but not APB, showed characteristic blastic morphology and significant expression of CD25 on the surface. A low concentration of IL-2 was detected at 24 h by anti-CD3-stimulated UCB CD4+CD45RA+, which rapidly disappeared. By 72 h after activation, CD4+CD45RA+ UCB cells showed extensive apoptosis, whereas CD4+CD45RA+ APB cells showed low levels of apoptosis. Using RNase protection assay, we observed that CD95L levels were significantly higher in naive CD4+ cells from UCB than from APB after activation. However, neutralizing Fas-Fc protein was unable to inhibit anti-CD3-induced apoptosis, suggesting that this was a CD95-independent mechanism. These results indicate that UCB-CD4+CD45RA+ cells are able to start proliferating as a result of early IL-2 production after TCR engagement alone, but probably, as a result of the consumption of this IL-2, they undergo cell death.

Similar Potential to Become Activated and Proliferate but Differential Kinetics and Profiles of Cytokine Production of Umbilical Cord Blood T Cells and Adult Blood Naive and Memory T Cells

“…Moreover, if the response measured in the UCB T cells would be partly derived from CD45RO ϩ T cells present in the UCB T-cell populations, the difference we observe here for CD45RA ϩ T cells from AB and CD45RA ϩ T cells from UCB would be even more pronounced. The proliferation data presented here are compatible with the findings from Canto et al [31], who showed similar proliferation for purified CD4 ϩ CD45RA ϩ T cells from UCB and CD4 ϩ CD45RA ϩ T cells from AB after stimulation with ␣CD3 and ␣CD28. However, these investigators found similar expression levels of CD25 for these CD4 ϩ CD45RA ϩ T-cell subpopulations and a relatively high level of apoptosis in UCB T cells.…”

Differential effect of IL‐15 and IL‐2 on survival of phytohemagglutinin‐activated umbilical cord blood T cells

“…In agreement of previous reports [8,9,28], we found an increased sensitivity of PHA-activated CB T cells to TNF-a-induced apoptosis compared to adults, which may contribute to the lesser degree of GVHD seen in CB transplantation. IL-15, but not IL-2, could rescue apoptosis of TNF-a-induced apoptosis of PHA-activated CB T cells, an effect not observed in APB T cells similarly activated.…”

Functional Maturation of CD4+CD25+CTLA4+CD45RA+ T Regulatory Cells in Human Neonatal T Cell Responses to Environmental Antigens/Allergens

“…Ag-dependent apoptosis exceeded the characteristically high spontaneous apoptosis that is a commonly described feature of in vitro cultured cord blood MNC (17)(18)(19). Naive murine neonatal T cells have also been shown to proliferate strongly (in the absence of up-regulation of activation markers) in response to nominal Ag, and this has been suggested to be mediated largely by low affinity interactions with self peptide/MHC, although a contribution from exogenous peptide could not be excluded (20).…”

“…A burgeoning body of literature highlights the intrinsic functional differences of fetal/neonatal vs adult naive T cells, and cord blood T cells can be considered to represent a transitional population between thymocytes and adult T cells (17). Likewise, the functions of cells arising from murine fetal thymic precursors are qualitatively and quantitatively different from those derived from the adult thymus (29).…”